The neural crest cell is well known for its migration capability to various locations within the developing embryo of vertebrates. This migration is mediated through several signaling pathways. Among these pathways, mutations in the RET and EDNRB pathways often manifest as human genetic diseases, such as Hirschsprung's disease (HSCR) and Waardenburg syndrome (WS). According to our preliminary data, one evolutionarily conserved zinc finger gene, Aebp2 (Adipocyte Enhancer Binding protein 2), may play a critical role in the migration of the neural crest cell. Aebp2 previously has been identifie as a regulator controlling the migration process of the border cell in Drosophila eggs, and also as a zinc finger protein co-purified with the mammalian Polycomb Repression Complex 2 (PRC2). Consistently, our recent studies reveal that a large fraction of Aebp2's genome-wide target loci overlap with the known PcG target loci, supporting the idea that Aebp2 is likely involved in targeting the mammalian PRC2. Interestingly, Aebp2 is mainly expressed within cells of neural crest origin, such as dorsal root ganglia, and facial cartilages and bones. Furthermore, according to the results derived from a mutant mouse line disrupting Aebp2, many heterozygotes display a set of phenotypes that are usually seen in human patients with Hirschsprung's disease and Waardenburg syndrome, for example megacolon and hypopigmentation. These phenotypes suggest that Aebp2 may be required for the migration and development of the neural crest cell. Given these observations, we hypothesie that Aebp2 may be an epigenetic regulator for the neural crest cell through PcG-mediated mechanisms. In the current proposal, we will test this hypothesis with the following aims: Aim1 will further characterize the molecular basis of the phenotypes observed from the Aebp2 heterozygotes, Aim2 will test potential involvement of the PRC2-mediated mechanism in the pathogenesis of WS and HSCR, and finally Aim3 will generate a conditional KO allele of the Aebp2 locus to further delineate Aebp2 roles in neural crest cell migration. The information derived from these experiments will be helpful in unraveling the in vivo roles of Aebp2 with a special focus on its potential roles in neural crest cell migration. This information should also provide a new epigenetic-based paradigm for the pathogenesis of the human neurocristopathies, Hirschsprung's disease and Waardenburg syndrome.